title: 99mTc-sestamibi is a substrate for P-glycoprotein and the multidrug resistance-associated protein.
abstract: 99mTc-sestamibi (99mTc-MIBI) is a substrate for the P-glycoprotein (P-gp) pump but it is not known whether it is a substrate for the multidrug resistance-associated protein (MRP) pump. Therefore, 99mTc-MIBI was evaluated in the GLC4 cell line and its doxorubicin-resistant MRP-, but not P-gp-, overexpressing GLC4/ADR sublines as well as in the S1 cell line and its MRP-transfected subline S1-MRP. 99mTc-MIBI concentration decreased in the GLC4/ADR sublines with increasing MRP overexpression and was lower in S1-MRP than in S1. 99mTc-MIBI plus vincristine increased 99mTc-MIBI concentration in GLC4 lines compared with 99mTc-MIBI alone. 99mTc-MIBI efflux raised with increasing MRP expression in the GLC4 lines. Glutathione depletion elevated 99mTc-MIBI concentration in GLC4/ADR150x. Cross resistance for 99Tc-MIBI, used to test cytotoxicity of the Tc compound, was observed in GLC4/ADR150x vs GLC4. 99Tc-MIBI induced a synergistic effect on vincristine cytotoxicity in GLC4/ADR150x. These results show that 99mTc-MIBI is involved in MRP-mediated efflux. The fact that 99mTc-MIBI efflux is influenced by MDR1 and MRP expression must be taken into account when this gamma-rays-emitting complex is tested for tumour efflux measurements.
authors.affiliation: PET-Center, Department of Internal Medicine, University Hospital Groningen, The Netherlands.
authors.forename: N H
authors.initials: NH
authors.lastname: Hendrikse
authors.forename: E J
authors.initials: EJ
authors.lastname: Franssen
authors.forename: W T
authors.initials: WT
authors.lastname: van der Graaf
authors.forename: C
authors.initials: C
authors.lastname: Meijer
authors.forename: D A
authors.initials: DA
authors.lastname: Piers
authors.forename: W
authors.initials: W
authors.lastname: Vaalburg
authors.forename: E G
authors.initials: EG
authors.lastname: de Vries
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D002470:Cell Survival / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D004317:Doxorubicin; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017256:Technetium Tc 99m Sestamibi